Immune System Offers Protection From Pain Early in Life

Early in life, anti-inflammatory molecules prevent the development of pain related to nerve injury in rodents, reports a study published January 14 in the Journal of Neuroscience. Led by Maria Fitzgerald of University College London, UK, in collaboration with Ru-Rong Ji at Duke University, Durham, US, the study found that, in young but not adult rodents, nerve injury raised levels of anti-inflammatory molecules, including the cytokines interleukin-4 (IL-4) and IL-10, in the spinal cord. Blocking IL-10 in the young unmasked hypersensitivity to touch due to the nerve injury.

“It isn't that young animals can't mount a pain response,” Fitzgerald told PRF. “Rather, they have an active suppression of it. If you remove the anti-inflammatory response, there the pain is.”

The work not only supports a role for cytokines, a class of small proteins that spur the immune system, in neuropathic pain (see PRF related news story), but it also highlights a mechanism that may protect young people from developing the condition.

Clinicians have observed that nerve injuries early in life rarely lead to neuropathic pain syndromes in childhood, unlike injuries suffered in adulthood. The new study suggests that a comparable anti-inflammatory response to injury in children may spare them from developing the hypersensitivities associated with neuropathic pain.

“It’s a pretty novel idea that IL-10 might be knocking down some of the potential responses to injury,” said Fletcher White of Indiana University, Indianapolis, US, who was not involved in the study. “I would not have predicted this result.” White studies interactions between the nervous and immune systems in pain.

But such protection may not last forever. For example, though some child amputees do not initially report phantom limb pain, it can eventually develop years after the trauma (Melzack et al., 1997). Other neuropathic pain syndromes arise at the earliest in adolescence, often with no identifiable cause.

The new study suggests that a trauma earlier in life could be to blame. Nerve injury in very young rodents led to a late-onset increase of pro-inflammatory molecules in adolescence, three weeks after the injury, coinciding with the development of neuropathic pain-like responses.

“We need to understand that it’s possible to develop chronic pain as a result of something that happened to you a long time ago,” Fitzgerald said.

Inflammatory switch

Fitzgerald and colleagues have previously modeled a delay in neuropathic pain development in rats. Ten-day-old rat pups given a partial nerve transection of the sciatic nerve did not develop the expected hypersensitivity to touch in the hindpaw until three weeks later, when they were effectively adolescents (Vega-Avelaira et al., 2012). In contrast, nerve injuries in adult rats gave rise to hypersensitivity within seven days.

In the new study, first author Rebecca McKelvey and colleagues expanded upon this, finding a delayed onset of sensitivity to cold and bearing weight on the affected hindpaw in neonatally injured rats and mice alike. Electrophysiological recordings from dorsal horn interneurons showed a corresponding profile of sensitivity, with relatively calm spiking activity in neonates but more excitable firing patterns in adolescents.

The researchers screened the dorsal horn for 40 different inflammation-related molecules to get clues about what might be changing in the spinal cord between early life and adolescence. They found that nerve injury in neonates initially spurred anti-inflammatory molecule release, but then later gave way to a pro-inflammatory profile in adolescence.

The anti-inflammatory molecules included IL-4, IL-10, and the transcription factor GATA3. Protein levels of IL-10 increased 40 percent after nerve injury. Nerve injury, however, was not required to trigger cytokine release: directly stimulating C fibers also evoked significant elevations of IL-4 and IL-10.

What cell actually produces IL-10 remains unclear, however, with nearby microglia, astrocytes, or even neurons themselves as candidates. White and colleagues have found that a chemokine called monocyte chemoattractant protein-1 (MCP-1) is packaged and released from sensory neurons just like a neurotransmitter (Jung et al., 2008).

“I don’t know of any situation where IL-10 or the IL-10 receptor is associated with sensory neurons,” White said. “But perhaps it’s because people have only looked in adults.”

A dormant pain

Blocking some of the anti-inflammatory response in neonates revealed pain responses, as though the spinal cord circuits had already changed to support hypersensitivity, but the concomitant pain responses remained dormant and unexpressed. The researchers showed that delivering a neutralizing antibody to IL-10 to the spinal cord activated touch hypersensitivity over the course of three days of injections.

In addition, adding pro-inflammatory players TNFα or activated microglia to the spinal cord revealed pain responses in the nerve-injured neonates. This suggests that the balance of anti-inflammatory and pro-inflammatory molecules can tilt a system away or toward the expression of neuropathic pain.

An anti-inflammatory response may prevail early in life to protect the developing nervous system and its steady stream of new receptors or other potentially immunogenic proteins from attack by the immune system, Fitzgerald suggests. “Then, as we get older, it becomes more advantageous to fight foreign antigens.”

Michele Solis is a science writer and former neuroscientist who lives in Seattle, Washington, US.